A disease group including liver disorders from simple fatty liver to steatohepatitis, fibrosis, and liver cirrhosis occurring at those without drinking history excluding viral liver diseases, autoimmune liver diseases, and metabolic liver diseases such as hemochromatosis and Wilson's disease is generally defined as non-alcoholic fatty liver disease (hereinafter abbreviated as NAFLD). NAFLD is further divided by liver biopsy (pathological finding) into simple fatty liver which is generally conceived to have a favorable prognosis and non-alcoholic steatohepatitis (hereinafter abbreviated as NASH) with unfavorable prognosis, and the NASH is considered to be the serious type of the NAFLD. The pathologies of the inflammation, fat accumulation, fibrosis or liver cirrhosis, and liver cancer determined to be NASH by the liver biopsy are the same as those caused by other causes, and many hepatitis cases which have been denied for the alcoholic liver disorder, viral hepatitis, and drug-induced liver injury are estimated to be the pathological conditions of the NASH. In the U.S., 20% of the population is estimated to suffer from the NAFLD, and 3% is estimated to suffer from the NASH. These are also diseases frequently encountered in Japanese general practice. Frequency of the NAFLD in medical examination is 8%, and the frequency of NASH is estimated to be at least 0.5 to 1% in the adult. In Japan, obese adults with BMI of 25 or more include 13 million men and 10 million women, and presence of 5 to million NAFLD patients and about 300 to 500 thousand NASH patients is estimated from these figures. Furthermore, in the case of the NAFLD, frequency of dyslipidemia complication is about 50%, frequency of hypertension complication is about 30%, frequency of hyperglycemia complication is about 30%, and frequency of metabolic syndrome complication is about 40% based on the diagnostic criteria of the metabolic syndrome, and from now on, increase in the number of NASH cases and expansion of the disease to younger people are estimated to take place with the increase of the lifestyle disease. In some patients, the liver disorder proceeds via the hepatitis to the liver cirrhosis or liver cancer by the activation of hepatic stellate cells, and this is clinically problematic. At present, histological diagnosis by liver biopsy is conceived to be necessary for definitive diagnosis of the NASH, and the histological diagnosis by the liver biopsy is also conceived to be necessary for the diagnosis of the healing of the disease. Liver biopsy is associated with the problem of heavy physical burden for both patients and medical professionals, and there is a strong demand for the establishment of a characteristic blood marker which is useful for the diagnosis and evaluation of the pathological conditions of the NAFLD and the NASH which can be used instead of the liver biopsy requiring the invasion. In addition, there is no established therapeutic method at present for the NASH while various treatments are attempted for improving the pathological conditions of the NASH and their effectiveness is reported (see Non-Patent Literature 1).
Examples of the blood test index which has been used for detecting the NASH include aspartate aminotransferase (hereinafter also referred to as AST), alanine aminotransferase (hereinafter also referred to as ALT), AST/ALT ratio, serum ferritin, serum thioredoxin, HOMA-IR, platelet count, TNFα, adiponectin, leptin, high sensitivity CRP, hyaluronic acid, type IV collagen 7S, procollagen III polypeptide, and CK18 fragment.
Also reported is increase of TNFα and CCL2/MCP-1 in the NASH patients compared to the patients of simple fatty acid (see Non-Patent Literature 2).
It has also been reported that when telmisartan (see Non-Patent Literature 3) or olmesartan (see Non-Patent Literature 4) was administered to a NASH model animal, fibrosis of the liver was suppressed, and this also led decrease in the expression of TIMP1 and TIMP2 mRNAs in the liver tissue (see Non-Patent Literature 3) or the expression of alpha 1[I] procollagen gene in the liver (see Non-Patent Literature 4).
In the gene analysis of liver cell in the liver cell-specific Pten knockout mouse which is a model animal for steatohepatitis and canceration of the liver, induction of adipsin, adiponectin, and the like was also reported (see Non-Patent Literature 5).
Also proposed is administration of a matrix metalloprotease (MMP) inhibitor to the NASH and the NAFLD (see Patent Literature 1).
Tanaka et al. examines amelioration of NASH by 12 month administration of high purity ethyl icosapentate (hereinafter also referred to as EPA-E). This study shows the results of liver biopsy after the EPA-E administration period, enzymatic observation using AST and ALT, and evaluation by inflammatory cytokines such as TNFα, sTNF-R1, and sTNF-R2 and oxidation stress markers such as thioredoxin (see Non-Patent Literature 6).